Technical Field
The present application relates generally to compositions for treating diseases that arise from inappropriate activity of proteins containing an acetyl-lysine. The compositions comprise a genus of cyclic vinylogous amides that are inhibitors of bromodomain.
Background Information
BRD4 is a member of the bromodomains and extra terminal domain (BET) family of proteins that recognize acetylated chromatin structures through their bromodomains and act as transcriptional activators. Brd4 functions as an associated factor and positive regulator of P-TEFb, a Cdk9-cyclin T heterodimer that stimulates transcriptional elongation by RNA polymerase II. Bromodomain-containing protein 4 (BRD4) contains two tandem bromodomains (BrD1 and BrD2) that bind preferentially to acetylated lysine residues found in histones and nonhistone proteins. This molecular recognition allows Brd4 to associate with acetylated chromatin throughout the cell cycle and regulates transcription at targeted loci.
Acute myeloid leukemia (AML) is a life-threatening stem cell disease characterized by uncontrolled proliferation and accumulation of myeloblasts. In a recent current study, Herrmann et al. [Oncotarget. 2012 December; 3 (12):1588-99] showed that inhibition of BRD4 by a small-molecule inhibitor, JQ1, leads to growth-inhibition and apoptosis in primary human AML stem- and progenitor cells, including cells derived from relapsed or refractory patients. In addition, JQ1 was found to induce apoptosis in CD34+/CD38− and CD34+/CD38+ stem- and progenitor cells in all donors. BRD4-inhibition is therefore recognized as promising new therapeutic approach in AML.
NF-κB-mediated inflammation is the major pathology in chronic kidney diseases, including HIV-associated nephropathy that ultimately progresses to end stage renal disease. HIV infection in the kidney induces NF-κB activation, leading to the production of proinflammatory chemokines, cytokines, and adhesion molecules. In a study published in the Journal of Biological Chemistry, Zhang et al. [J Biol Chem. 2012 Nov. 9; 287(46):38956] showed that a Bromodomain and Extra-Terminal domain-specific bromodomain inhibitor MS417 effectively ameliorated inflammation and kidney injury in HIV-1 transgenic mice, an animal model for HIV-associated nephropathy.
Thus, there is a need for inhibitors of BRD4 as therapeutic agents for leukemia and HIV-associated nephropathy.